Hypothalamic-pituitary-adrenal (HPA) axis activity is increased in Alzheimer's disease (AD) as manifested by increased concentrations of cortisol in plasma, urine and cerebrospinal fluid (CSF). Because cortisol elevations induced by exogenous cortisol administration or by stress produce hippocampal dendritic atrophy and may contribute to aging- associated hippocampal neuronal loss in several mammalian species, exposure of the brain to elevated concentrations of cortisol in AD may lower the threshold for neuronal degeneration in this disorder. In our preliminary data, presence of the apolipoprotein E (APOE)-E4 allele, which is the chief known genetic risk factor for AD, increases cortisol concentrations in CSF in both AD subjects and nondemented older subjects in a dose-dependent manner. In addition, presence of the E2 allele, which reduces AD risk, reduces CSF cortisol. These preliminary data raise the possibility that increased brain exposure to cortisol is a mechanism by which the APOE-e4 allele increases risk for expression of AD in later life. If one assumes that the human APOE-E4 allele produces at least partial aging-dependent loss of normal apoE function, then recent studies in transgenic mice also support this possibility. ApoE-deficient knockout mice (APOE -/-) have aging-related increases in corticosterone (the rodent glucocorticoid [GC](equivalent of cortisol) accompanied by brain neurodegenerative changes in hippocampus and neocortex. In this application, we propose to confirm and extend our preliminary finding that APOE-E4 increases CSF cortisol in an aging-dependent manner, and to determine if the neuroendocrine mechanism for this phenomenon is increased responsiveness of the adrenal cortex in older persons with the E4 genotype. We also propose to follow longitudinally nondemented older persons carrying the E4 allele to determine if those with higher CSF cortisol concentrations are more likely to develop cognitive decline and AD. We have chosen to measure cortisol in CSF because of our preliminary findings demonstrating that cortisol in CSF provides a more integrated measure of cortisol release over time than does cortisol measured in plasma or saliva, and because CSF cortisol provides a likely estimate of brain neuron exposure to biologically-active free cortisol. We will pursue the following Specific Aims: Specific Aim 1. To determine the effect of APOE genotype on CSF cortisol concentrations in persons with AD, nondemented older persons, and young and middle-aged persons. Specific Aim 2. To determine the effect of the APOE-E4 allele on the plasma cortisol response to exogenous adrenocorticotrophic hormone. Specific Aim 3. To determine the effect of CSF cortisol concentrations on cognitive decline and on incidence of mild cognitive impairment and probable AD among nondemented older persons with the APOE-E4 allele followed longitudinally.